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Kohlschutter-Tonz syndrome: mutations in ROGDI and evidence of genetic heterogeneity.

ABSTRACT: Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease.

SUBMITTER: Tucci A

PROVIDER: S-EPMC3902979 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Kohlschütter-Tönz syndrome: mutations in ROGDI and evidence of genetic heterogeneity.

Tucci Arianna A Kara Eleanna E Schossig Anna A Wolf Nicole I NI Plagnol Vincent V Fawcett Katherine K Paisán-Ruiz Coro C Moore Matthew M Hernandez Dena D Musumeci Sebastiano S Tennison Michael M Hennekam Raoul R Palmeri Silvia S Malandrini Alessandro A Raskin Salmo S Donnai Dian D Hennig Corina C Tzschach Andreas A Hordijk Roel R Bast Thomas T Wimmer Katharina K Lo Chien-Ning CN Shorvon Simon S Mefford Heather H Eichler Evan E EE Hall Roger R Hayes Ian I Hardy John J Singleton Andrew A Zschocke Johannes J Houlden Henry H

Human mutation 20121127 2

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in fiv ...[more]

PMID: 23086778

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Project description:PurposeThis study reported the first case of Kohlschütter-Tönz syndrome (KTS) in China and reviewed the literature of the reported cases.MethodsThis patient was registered at the Children's Hospital of Chongqing Medical University. The patient's symptoms and treatments were recorded in detail, and the patient was monitored for six years. We employed a combination of the following search terms and Boolean operators in our search strategy: Kohlschütter-Tönz syndrome, KTS, and ROGDI. These terms were carefully selected to capture a broad range of relevant publications in PubMed, Web of Science, WHO Global Health Library, and China National Knowledge Infrastructure, including synonyms, variations, and specific terms related to KTS. The pathogenicity of the variants was predicted using SpliceAI and MutationTaster, and the structures of the ROGDI mutations were constructed using I-TASSER.ResultsThis is the first case report of KTS in China. Our patient presented with epilepsy, global developmental delay, and amelogenesis imperfecta. A trio-WES revealed homozygous mutations in ROGDI (c.46-37_46-30del). The brain magnetic resonance imaging (MRI) and video electroencephalogram (VEEG) were normal. The efficacy of perampanel (PMP) in treating seizures and intellectual disability was apparent. Furthermore, 43 cases of ROGDI-related KTS were retrieved. 100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta. 17.2% received a diagnosis of attention deficit hyperactivity disorder (ADHD), and 3.4% were under suspicion of autism spectrum disorder (ASD). Language disorders were observed in all patients. Emotional disorders, notably self-harm behaviors (9.1%), were also reported.ConclusionROGDI-related KTS is a rare neurodegenerative disorder, characterized by three classic clinical manifestations: epilepsy, global developmental delay, and amelogenesis imperfecta. Moreover, patients could present comorbidities, including ADHD, ASD, emotional disorders, and language disorders. PMP may be a potential drug with relatively good efficacy, but long-term clinical trials are still needed.

Dataset Information

Kohlschutter-Tonz syndrome: mutations in ROGDI and evidence of genetic heterogeneity.

Publications

Kohlschütter-Tönz syndrome: mutations in ROGDI and evidence of genetic heterogeneity.

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